The goal of the proposed project is to investigate mechanisms of pathogenesis and immunoregulation in autoimmune type 1 diabetes through the use of a T cell receptor transgenic (TCR-Tg) mouse expressing the alpha and beta chain genes from the T cell receptor of an islet specific, diabetogenic T cell clone, BDC-6.9. The T cell clone, BDC-6.9, is similar to another clone in our panel, BDC-2.5, in that it was derived from spleen cells of an NOD mouse, reacts with an antigen in the beta granule membrane, and rapidly induces disease when administered to young NOD mice or to NOD-scid recipients. The BDC-6.9 clone, unlike BDC-2.5, responds to islet antigen only from NOD or NOD-related mice and we have identified a microsatellite marker which is closely linked to the BDC-6.9 antigen on chromosome six. We have taken advantage of these findings to produce an NOD congenic (NOD.C6) mouse that lacks the BDC-6.9 autoantigen. Our aims under this project are to (1) characterize the properties of the 6.9 TCR-Tg mouse on the NOD background with respect to T cell function and disease incidence, (2) breed and characterize the 6.9 TCR-Tg mouse on the NOD.C6 congenic mouse lacking the target antigen, and (3) define the antigen for the BDC-6.9 antigen through analysis of differential gene expression in islets from NOD and NOD.C6 mice.